Recent advances in diagnosing, managing, and understanding the pathophysiology of cluster headache.

Cluster headache, characterised by attacks of severe, recurrent, unilateral headache and ipsilateral cranial autonomic symptoms, remains a primary headache with an elusive pathophysiology. Recent advances have introduced effective treatments and broadened understanding of the clinical features of cluster headache. These features are similar in patients globally, but regional differences in prevalence and burden exist. International collaborations have led to identification of eight genetic loci associated with cluster headache. The pathophysiological mechanisms are still not fully understood but recent studies show that targeting the trigeminal autonomic reflex by neurostimulation, or targeting the neuropeptide calcitonin gene-related peptide (CGRP), might lessen the attack burden. The US Food and Drug Administration has approved galcanezumab, a monoclonal antibody targeting CGRP, as the first specific preventive treatment for episodic cluster headache. However, a preventive effect was not replicated in chronic cluster headache, and the European Medicines Agency did not approve galcanezumab, restricting its availability in Europe. Owing to the low prevalence of cluster headache, continued collaboration through multicentre clinical trials and data sharing will be imperative for further breakthroughs in understanding and management.
Competing Interests: Declaration of interests ASP has received a restricted research grant (payment to their institution) and conference attendance from Lundbeck Pharma, and personal fees from Pfizer for teaching activities. NL has received a restricted research grant from Lundbeck Pharma (payment to their institution), a research grant from the Capital Region Research Foundation, support for conference attendance from Pfizer, and personal fees from teaching activities for general practitioners from Dagens Medicin and Pfizer (personal). PJG reports, over the past 36 months: grants from Celgene and Kallyope; personal fees from Aeon Biopharma, AbbVie, Amgen, eNeura, CoolTech, Dr Reddys, Eli Lilly, Epalex, Linpharma, Lundbeck, Novartis, Pfizer, Sanofi, Satsuma, Shiratronics, and Teva Pharmaceuticals; participation on a data and safety monitoring board for Aeon Biopharma and Man & Science; personal fees for advice through Gerson Lehrman Group, Guidepoint, SAI Med Partners, and Vector Metric; fees for educational materials from CME Outfitters; publishing royalties or fees from Massachusetts Medical Society, Oxford University Press, UptoDate, and Wolters Kluwer; and a patent for magnetic stimulation for headache (WO2016090333 A1) assigned to eNeura, without fee. PJG is a board member of the American Headache Society, Migraine Trust, and Organisation for Understanding Cluster Headache. ACB reports honoraria for presentations from Novartis, Teva, and Lundbeck; and research funding from the Swedish Brain Foundation and the Mellby Gård Foundation. S-JW has received honoraria as a moderator from AbbVie, Biogen, Eli Lilly, Hava Biopharma, and Pfizer; has received consulting fees from AbbVie, Eli Lilly Taiwan, Percept, and Pfizer Taiwan; and has received research grants from the Taiwan branches of Eli Lilly, Lundbeck, Novartis, and Orient Europharma. RF reports research grants from Bioprojet, Jazz Pharmaceuticals, Netherlands Brain Foundation, and ZonMW (fee for institution); educational honoraria from Novartis (fee for institution), Teva Pharmaceutical Industries, Bioprojet, and Lundbeck Pharma (personal fees); consultancy for AbbVie, Eli Lilly, and Takeda (fee for institution); and is a member of the cluster headache section of the Dutch Headache guidelines (unpaid). MB reports grant funding from the Will Erwin Headache Research Foundation; travel support for attending meetings from the American Headache Society; has served as a consultant for Lundbeck, Beckley Psytech, Praxis Precision Medicines, and PureTech Health; is a site investigator for a cluster headache clinical trial funded by Lundbeck; was a paid guest for a video podcast by the American Academy of Neurology, is a paid survey respondent for Doximetry, and is an unpaid member of the medical advisory board of Clusterbusters. S-JC was involved as a site investigator of a multicentre trial sponsored by Allergan, AbbVie, Hyundai Pharmaceutical, Ildong Pharmaceutical, Eli Lilly, Pfizer, and Lundbeck; and has received lecture fees or advisory honoraria from AbbVie Korea, Lundbeck, Eli Lilly Korea, SK Chemicals, Teva Pharmaceutical Industries, and Pfizer. MFPP reports consulting fees for AbbVie–Allergan, Ache, Eli Lilly, Eurofarma, Libbs, Lundbeck, Kenvue, Pfizer, Sanofi-Aventis, and Teva Pharmaceutical Industries; travel support from Teva; participation in advisory boards for AbbVie-Allergan, Eli Lilly, Pfizer, Kenvue, Eurofarma, and Sonofi-Aventis; and is president of the Brazilian Association for Cluster Headache and Migraine (unpaid). RHJ received a restricted research grant (for institution) for work on cluster headache from Lundbeck Pharma; received a research grant for treatment trial for idiopathic intracranial hypertension (for institution) from Novo Nordisk Foundation; is on an advisory board for Lundbeck Pharma and has received fees for participation on an advisory board (for institution); has received personal fees for educational and teaching activities from Pfizer, Teva Pharmaceutical Industries, Novartis, AbbVie, Lundbeck, and Eli Lilly; is chair of the Master of Headache Disorders at the University of Copenhagen, a director of the Danish Headache Center, and undertakes unpaid activities as a director of Lifting The Burden.
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